Polyamine compounds

ABSTRACT

Novel diphenyl and loweralkyl substituted diphenyl polyamines are useful antimicrobial agents, as well as algae inhibitors. They are especially useful because of their low toxicity, and as such are advantageously included as the active agent in surgical scrubs, antibacterial soaps, as preservatives in cosmetic preparations, and the like. They also can be used for topical treatment of dermatological conditions having a bacterial origin or implication such as Acne vulgaris.

DISCLOSURE OF THE INVENTION

This invention relates to a new class of polyamines which are useful asbroad spectrum antimicrobial agents, as well as algae inhibitors. Theyare especially useful because of a surprisingly low toxicity and areparticularly suitable for topical use including use in dermatologicaland cosmetic preparations, as well as surgical scrubs and hard surfacedisinfectants. These novel compounds have the structural formula:##STR1## where each A is alike or different and is ##STR2##

each R is alike or different and is hydrogen or loweralkyl;

EACH N IS ALIKE OR DIFFERENT AND IS THE INTEGER 0 OR 1;

EACH R₁ is alike or different and is C₁ to C₄ alkylene; ##STR3## and

R₂ is 2-hydroxy-1,3-trimethylene, or R₁ as previously defined;

R₃ is hydrogen, C₁ to C₄ alkyl, C₂ to C₄ aminoalkyl or C₁ to C₄hydroxyalkyl, C₂ to C₄ dihydroxyalkyl, e.g., 2,3-dihydroxypropyl and3,4-dihydroxybutyl; and

R₄ is 2-hydroxy-1,3-trimethylene, or R₁ as previously defined;

R₅ is hydrogen, aminoethyl, aminopropyl, C₁ to C₄ hydroxyalkyl, or C₂ toC₄ dihydroxyalkyl; and

R₆ is hydrogen, C₁ to C₄ hydroxyalkyl or C₂ to C₄ dihydroxyalkyl;

OR WHEN R₃ and R₆ taken together are ethylene, R₄ is also ethylene, andR₅ is aminoethyl, aminopropyl, or aminohydroxypropyl;

The compounds of this invention are preferably prepared according to thefollowing sequence of reactions: ##STR4## where A, Z and n have theirpreviously defined meanings, HX is a mono or polybasic organic orinorganic acid, where sufficient HX is provided to protonate at leastone amino group of phenyl polyamine compound I, to form salt I(a).

The preparation of phenyl polyamine I comprises the Schiff base reactionof the appropriate ketone IV and the appropriate amine V.

If amine V has two primary amino groups, it can either be symmetrical orunsymmetrical. An amine V, which is a symmetrical amine, e.g., where R₂and R₄ are alike when R₅ and R₆ are hydrogen forms a single Schiff baseVI. This is because regardless of which terminal primary amine group ofamine V reacts with ketone IV, the same product results. However, whereamine V is unsymmetrical at least two products can result. For example,if Y is ##STR5## and R₅ is either aminoethyl or aminopropyl, there isobtained Schiff base VI ##STR6## as well as Schiff base VI(a) ##STR7##where A, R₁₋₆ and n are as previously defined. Note that both productsVI and VI(a) come within the scope of the definition given for Schiffbase VI. Where multiple products such as Schiff bases of formulas VI andVI(a) are produced, they can be separated, if desired, by the usual andwell known separation techniques, i.e., distillation and the like.

As an alternative to obtaining a mixture of Schiff bases VI and VI(a) orVI(b), which upon reduction give a mixture of product I the reaction canbe conducted stepwise. For example, 1,4-diaminobutane or4-(2-aminoethyl)piperazine may be converted to a Schiff base with1,5-di-(4-isopropyl)-phenyl)-3-pentanone, catalytically reduced, thenthe resulting amine selectively cyanoethylated with acrylonitrile,followed by catalytic hydrogenation to furnish1-(3-amino-propyl)-4-[1,5-di-(4-isopropylphenyl)-3-pentyl]diaminobutane,a spermidine derivative, or1-(3-aminopropyl)-4-[2-{(1,5-di-(4-isopropylphenyl)-3-pentylamino}ethyl]piperazine.A primary amine can be dicyanoethylated with excess acrylonitrile,catalytically reduced to the corresponding 3,3'-substitutediminobis(propylamine) and then converted by condensation with a ketoneand reduction to the N-alkylated-3,3'-substituted iminobis(propylamine).For example, dicyanoethylation of monoethanolamine followed by catalyticreduction provides 3,3'-(2-hydroxyethylimino)bis(propylamine).Condensation with1-(2,4-dimethylphenyl)-6-(3-isopropylphenyl)-3-hexanone and subsequentcatalytic hydrogenation of the --C═N bond affords1-[1-(2,4-dimethylphenyl)6-(3-isopropylphenyl)-3-hexyl]-5-(2-hydroxyethyl)-1,5,9-triazanonane.

To prepare Schiff base VI, ketone IV and amine V are dissolved in asuitable inert solvent, for example, toluene, and heated to reflux,until reaction is substantially complete. Usually 5 to 20 hours issufficient for water removal by azeotropic distillation. The solvent isthen removed under reduced pressure and the residue comprising theSchiff base VI is dissolved in an inert solvent preferably an alkanol,such as ethanol or isopropanol.

After dissolution, the Schiff base VI is catalytically or chemicallyreduced.

In catalytic reductions, hydrogen saturates an alkanol solution ofSchiff base VI using agitation in the presence of the usualhydrogenation catalysts, such as transition metals and their reducibleoxides. Especially effective catalysts are the noble metals and theiroxides. A particularly preferred catalyst is platinum oxide. Generally,the hydrogenation reaction is carried out in a manner well known in theart. Small particles, e.g., 100-300 mesh of catalyst are admixed withthe Schiff base and excess amine in alcohol and placed in a closedsystem pressurized with from 3-5 atmospheres of hydrogen gas. Afterreaction is complete, the pressure is released and the catalystseparated from the reaction mixture by filtration. The filtratecontaining the phenyl polyamine I, is then futher purified by usualtechniques. Preferably, whatever solvent may be present is removed underreduced pressure, the residue then dissolved in a water-immisciblesolvent, washed with water, followed by a further washing with asaturated aqueous inorganic salt solution. After drying, the solvent isremoved by evaporation under reduced pressure giving the phenylpolyamineI usually as an oil. The phenylpolyamine can then be redissolved inloweralkanols, mixtures of loweralkanols and water, diethylether,dioxane and then neutralized with an acid, e.g., hydrogen chloride, orneutralized directly with aqueous acids.

Acid addition salts I(a) are then isolated, if desired, byprecipitation, evaporation or other usually employed techniques.

Suitable anions X for the salt I(A) include anions derived frominorganic acids as well as those of organic acids such for example ashalide, i.e., chloride, bromide or iodide or sulfate, nitrate,bisulfate, phosphate, acetate, propionate, maleate, succinate, laurate,palmitate, oleate, stearate, ascorbate, gluconate, citrate, carbonate,bicarbonate, benzoate, salicylate, pamoate, phthalate, furoate,picolinate, dodecylbenzenesulfonate, laurylethersulfate, nicotinate andthe like. Generally, any anion derived from an acid is suitable andsatisfactory when the polyamine salt anion X⁻, e.g., chloride isreplaced with other anions, by well known anion exchange techniques.

Alternatively, a chemical rather than a catalytic reduction is employedto reduce Schiff base VI to product I.

In this chemically reductive procedure, the ketone IV is reacted withthe appropriate amine as before, but the Schiff base VI dissolved in analkanol or inert ether-type solvent is reacted with a chemical reductantsuch as sodium borohydride or lithium aluminum hydride, respectively.

Although as little as an equivalent of the chemical reductant can beused successfully, more satisfactory results are obtained if at leasttwo molar excess of and preferably at least a 2.5 molar excess of thechemical reductant is employed. After any initial reaction has subsided,the reaction mixture may be heated at reflux for an hour or two, thencooled to room temperature, and afterwards concentrated under vacuum.The residue obtained is then further purified as by treatment withmineral acid or inorganic base as was described for polyamines I and thesalt may thereafter be formed as previously described.

The diphenyl ketones IV are readily prepared and two alternativemethods, are set forth below.

(A) The condensation of Acids-- This method involves the followingreaction scheme: ##STR8##

Acylative decarboxylation of acids VII is employed by heating the acidat elevated temperatures either with transition metals, preferably iron,transition metal oxides, alkaline earth oxides, with polyphosphoric acidor with boron trifluoride. Most suitably, acylative reaction is achievedby passage of acid vapors over catalysts such as heated thoria aerogel.

Condensation-decarboxylation of an acid is the preferred method forpreparing ketone IV when each A--(R₁)_(n) group is alike and n=1, amixture of products being obtained when several different acids arecombined in a reaction. The preferred reaction comprises admixingcarboxylic acid VII with reduced iron powder and stirring in an inertatmosphere at 195° C. to 200° C. for 1-6 hours to form an iron salt.

Preferably, the carboxylic acid VII and iron are agitated under an inertatmosphere of nitrogen for at least 2 hours at 195° C. to 200° C.

After 2 hours, the temperature is increased suitably to 290° C. to 310°C. and agitation continued for at least another three hour period, fourhours usually being sufficient. The reaction mixture is allowed to cool,and then is extracted with a suitable inert solvent such as diethyletherand filtered. The solvent extracts are concentrated under reducedpressure. The residual liquid is distilled under vacuum to isolate theketone IV.

The carboxylic acids VII employed above are prepared by various meanswell known in the art.

(B) Condensation of a Grignard and a Nitrile

Diphenyl alkanones can be obtained according to the following reactionscheme: ##STR9## where A or (R_(l))_(n) of each reactant may be the sameor different and are as previously defined.

This general procedure utilizes the reaction of a Grignard reagentprepared from a chloro- or bromo-substituted phenyl derivative with acyanosubstituted phenyl derivative. The resultant disubstitutediminoalkane Grignard complex is hydrolyzed with aqueous mineral acid tothe corresponding ketone.

The Grignard reagent is obtained by reaction of the halide withmagnesium metal, usually in the form of turnings or powder and may becatalyzed by very small concentrations of iodine or methyl iodide.Solvents which are useful include diethyl ether, dibutyl ether,tetrahydrofuran, dioxane and benzene. Usually, gentle warming sufficesto initiate the reaction and the halide is gradually added to themetal-solvent mixture. After complete addition the disappearance ofpractically all magnesium metal signifies the end of the reaction. Asmall excess of halide is used and moisture must be excluded; a nitrogenatmosphere is beneficial. The Grignard reagent is then added to thenitrile, which is previously dissolved in two or three times its volumeof solvent, over a period of 15 minutes to 1 hour at ambienttemperature. The reaction mixture may then be heated to reflux to insurecomplete reaction. Generally, a small excess of Grignard reagent ascompared to nitrile is employed. From 1 to 10 hours at reflux issufficient for complete conversion. The resultant imine salt ispreferably decomposed and hydrolyzed to the ketone with aqueous mineralacids such as hydrochloric, sulfuric and phosphoric. The ketones arewater-insoluble and may be extracted with water-immiscible solvents.Purification is preferably accomplished by fractional distillation underreduced pressure. It is feasible to use the crude ketone reactionmixture for the alkylation of polyamines as the Grignard reactionby-products are usually alcohols or hydrocarbons and do not react withamines. The raeactant halides, if present in the crude product, shouldbe removed prior to the ketone-amine alkylation process.

The concentrations of Grignard reagent and nitrile may be varied overwide limits for securing good yields in the process. The halide andcyano, as well as carboxylic derivatives of phenyl compounds, e.g.,phenylacetic acid are readily available.

Once the ketone IV is obtained it can then be reacted with a suitablepolyamine V. Polyamines V which are exceptionally suitable for reactionwith ketone IV include diethylenetriamine, triethylenetetramine,3,3'-iminobis-(propylamine), 3,3'-methyliminobis-(propylamine),dipropylenetriamine, N,N'-bis-(3-aminopropyl)-1,3-trimethylenediamine,N,N'-bis-(2-aminoethyl)-1,3-trimethylenediamine,N,N'-bis-(3-aminopropyl)piperazine,N-(3-amino-2-hydroxypropyl)-1,3-trimethylenediamine,N-(2-aminoethyl)-1,3-trimethylenediamine, spermidine, spermine,1,4-bis-(2-aminoethyl)piperazine, tris-(2-aminoethyl)amine,1-(2-aminoethyl)-4-(3-aminopropyl)piperazine,1-(3-amino-2-hydroxypropyl)-4-(2-aminoethyl)piperazine,1-(2,3-dihydroxypropyl)-1,5,9-triazanonane,1-(2-hydroxyethyl)-1,4,7,10-tetraazadecane,4-(3,4-dihydroxybutyl)-1,4,8-triazaoctane,1-(2-hydroxypropyl)-5-hydroxymethyl-1,5,9-triazanonane,tris-(3-aminopropyl)amine, ethylenediamine, trimethylenediamine, and1,3-diamino-2-hydroxypropane.

The compounds described herein are excellent broad spectrumantimicrobial agents which are especially effective against grampositive and negative bacteria, particularly troublesome gram-negativemembers of the genus Pseudomonas at aqueous concentrations of 1.0 to 100ppm. Examples of susceptible species include, inter alia, Staphylococcusaureus, Streptococcus pyogenes, Bordetella bronchiseptica,Corynebacterium acnes, Pasteurella multocida, Escherichia coli,Salmonella typhimurium, S. pullorum, Klebsiella pneumoniae, Aerobacteraerogenes, Pseudomonas aeruginosa, Desulfovibrio desulfuricans, Bacillusmycoides, fungi such as Aspergillus niger and Chaetomium globosum andyeast such as Candida albicans.

The low toxicity of these compounds makes them especially attractive foruse where contact with skin surfaces or possible ingestion renders theuse of irritating or toxic materials inadvisable. Exemplary toxicity ofa representative number of compounds is tabulated in Table I below.

                  TABLE I                                                         ______________________________________                                                                Acute Oral                                            Compound                LD.sub.50 mice                                        ______________________________________                                        1-[1,7-di-(2-methyl-5-t-butylphenyl)-                                                                 1650 mg./kg.                                          hydrochloride                                                                 1-[1,7-di-(2-methyl-5-t-butylphenyl)-                                                                 2070 mg./kg.                                          4-heptyl]-1,4,7,10-tetrazadecane                                              tetrahydrochloride                                                            1-[1,7-bis-(4-t-butylphenyl)-4-heptyl]-                                                               1550 mg./kg.                                          1,5,9,13-tetrazatridecane tetra-                                              hydrochloride                                                                 1-[1,5-di-(2,4,6-trimethylphenyl)-3-                                                                  1150 mg./kg.                                          pentyl]-1,5,9-triazanonane tri-                                               hydrochloride                                                                 ______________________________________                                    

For use, these compounds can be applied neat or employed in a dilutedform. Satisfactory diluents include any inert material not destructiveof the antimicrobial activity and especially liquid formulationscomprising aqueous dispersions, solutions, and emulsions. Solid diluentsinclude talc, corn starch, alumina and diatomaceous earth. Theantimicrobial agents of this invention can also be deposed on materialssuch as natural fibers including paper, cotton, wool and syntheticfibers such as nylon, polypropylene, as well as upon inanimate surfacesincluding hard surfaces such as wood, glass, metal, tile, rubber,plastic, and porous surfaces such as concrete, leather and the like.

The polyamines of this invention are especially useful in suppressingthe growth of aerobic and anaerobic bacteria in fluids employed incutting and grinding operations, such as metal working, and oil welldrilling muds or secondary oil recovery waters and brines. Anaerobessuch as the sulfate-reducer, Desulfovibrio desulfuricans, are inhibitedat 0.1-10 ppm. concentration of these polyamines. Suppression of thesebacteria eliminates hydrogen sulfide production and corrosion ofequipment, plugging of oil-bearing sands, malodors and other deleteriousactions. These compounds are also useful in the preservation againstbiodeterioration of other aqueous systems such as aqueous emulsions anddispersions, paints or coatings, pigment suspensions, adhesives and thelike where proliferation of microorganims can produce colloid breakdown,pH shifts, malodors, corrosive substances, viscosity loss and otherundesirable effects.

One particularly useful application of the compounds of this inventionis imparting sanitizing properties to fabrics, either woven ornon-woven, launderable or disposable, which are to be employed, such forexample, as diapers, surgical masks, caps, gowns, towels and drapes,covers for hospital furniture or instrument wrappings, aseptic facialtissues and sanitary napkins and bathroom tissue. In this application,the compounds of Formula I can be applied to the fibrous pulp beforeextracting or strand or thread formation or it can be sprayed upon thefinished goods. Either deposition technique is satisfactory so long asfrom 1×10⁻⁴ % or more by weight of the antimicrobial material isretained on the cloth. Greater than 0.1% to 1% by weight is generallyexcessive and superfluous.

Another application is alone or in solution or suspension or inconjunction with soaps or detergents for use in cleansing the skin,particularly in presurgical scrubbing formulations, or in formulationsfor controlling the growth of Corynebacterium acnes. C. acnes is astrain of bacteria implicated in acne conditions, especially Acnevulgaris. Applications of as little as 1 to 5 ppm. is effective incontrolling such skin dwelling bacteria. Larger concentrations can beused if desired without irritation or discomfort such as 2500 ppm andhigher. Where the cleansing formulation is diluted with water upon use,the formulation can comprise from 0.01% by weight and more of thepolyamine of this invention.

In addition, the compounds described herein can be employed in impoundedwater, such as swimming pools, ponds or industrially-used water such ascooling or papermill water to inhibit growth of undesirable bacteria,fungi, and/or algae.

In the control of slime-producing microorganisms and algae inrecirculating industrial waters, particularly cooling operations andespecially installations such as cooling towers, the polyamine compoundsof this invention are usually employed alone, but can also be used incombination with other antimicrobial agents. The compounds arepreferably employed as salts to enhance solubility. Concentrations inthe recirculating water of as little as 1×10⁻⁴ % by weight are effectivein inhibiting microbial growth. To insure effectiveness, especiallyagainst more resistant strains of microorganisms, and also when make-upwater is added to replace water lost by evaporation and the like,concentrations of from 1×10⁻⁴ % to 5×10⁻² % by weight are mostsatisfactory. Dosage may be continuous or as intermittent "shocktreatment", i.e., addition in a 10-20 minute period every 4-8 hours.

An unusual, highly advantageous property of these compounds is highsubstantivity to all kinds of surfaces; this provides protection againstcorrosion and acts as a storage depot for continuously dosing the watersin contact. The same properties also are largely responsible for thepreviously stated utility as disinfectants for inanimate surfacescomprising walls and ceilings, equipment, animal pens, hospitalfacilities, kitchens and bathrooms and the like, and can be convenientlyapplied as a spray or an aerosol.

In formulating the compounds of this invention for the above uses, thesecompounds can be employed in combination with other antimicrobialagents, surfactants, insecticides, defoamers, odorants, or as chelatesof metals such as copper, calcium, magnesium and iron.

Agricultural uses for these compounds include the control of microbialdamage to plants and seeds by application to the involved surface areas.The compounds of this invention show high orders of bacterial inhibitionand are especially useful for this purpose. Some of the diseases whichare of commercial importance in decreasing yield and quality and arecontrolled by the compositions of the invention are fire blight of appleand pear, bacterial spot on stone fruit, cherry leaf spot, walnutblight, common blight of bean, bacterial spot of tomato and pepper, andpotato seed piece decay. The effective concentration of polyaminesrequired varies from 5-100 parts per million; they may be applied asdusts, powder dispersions, aqueous solutions, emulsions in water, or asaqueous dipping baths. Other plant diseases which can be controlled bytreatment with these formulations are fungal in origin, such as the manykinds of powdery mildew and leaf scabs.

For seed treatment, proportions as low as 1 to 4 ounces per hundredweight (550 to 600 ppm on seed) are effective against various fungi.

For agricultural uses, the compounds of the invention are most suitablyused in the form of aqueous suspensions or emulsions, the free baseproducts being generally insoluble in water. For this type offormulation various powdered carriers can be employed to aid inachieving uniform distribution. Talc, fuller's earth, calcium silicate,calcium carbonate, clays and the like are admixed with the agent alongwith wetting and dispersing agents and sticking agents. For maximumchemical compatability those which are non-ionic in character arepreferred. Other anionic or cationic surfactants are also satisfactory.

Additional applications for the compounds of this invention includeinhibiting formation of dental plaque especially when used as an oralrinse, e.g., a mouth wash, or in combination with a toothpaste or toothpowder containing from 50-1,000 ppm.

The following specific examples are further illustrative of ourinvention, but should not be construed as any limitation on the compoundpresented in formula I or the appended claims.

EXAMPLE A Preparation of 1,5-Di-(4-Isopropylphenyl)-3-pentanone

3-(4-Isopropylphenyl)propionic acid (0.20 mole) and iron (hydrogenreduced, 6.15 g., 0.11 mole) are heated for 1.5 hours at 195° C. under anitrogen atmosphere. After that time, the temperature is increased to290° C. and maintained at that temperature for three hours. The cooledreaction mass is extracted well with ether, filtered through Celite, andthe ethereal extracts concentrated under vacuum. The residue is strippedunder vacuum to leave the product, 17.3 g. (51%).

In an analogous manner there are obtained the following ketones.

1,7-Di-(4-isopropylphenyl)-4-heptanone;

1,9-Diphenyl-5-nonanone;

1,5-Diphenyl-3-pentanone;

1,3-Diphenylacetone;

1,3-Di-(4-isopropylphenyl)acetone;

1,7-Diphenyl-4-heptanone;

1,3-Di-(4-t-butylphenyl)acetone;

1,7-Di-(4-ethylphenyl)-4-heptanone;

1,7-Di-(2-methyl-5-t-butylphenyl)-4-heptanone;

1,5-Di-(2-isopropylphenyl)-3-pentanone;

1,5-Di-(2,4,6-trimethylphenyl)-3-pentanone;

1,9-Di-(2-ethylphenyl)-5-nonanone;

1,5-Di-(4-t-butylphenyl)-3-pentanone;

1,5-Di-(4-methylphenyl)-3-pentanone;

1,7-Di-(4-t-butylphenyl)-4-heptanone.

EXAMPLE B Preparation of 4-Phenyl-1-(4-isopropylphenyl)-butanone-2

A Grignard reagent was prepared from 2-phenylethyl bromide 21 gm. (0.11mole) and magnesium, 2.4 g. (0.1 gram atom). The magnesium is coveredwith 25 ml. of anhydrous ether, a crystal of iodine added and in anitrogen atmosphere, the halide dissolved in 50 ml. of anhydrous etheris added, once initial reaction is obtained, at reflux temperature overa period of 1-2 hours. After complete addition, refluxing is continuedfor 1/2 hour.

In a nitrogen atmosphere, the Grignard solution is clarified by passagethrough a glass wool filter plug and added slowly to an agitatedsolution of 4-isopropylphenylacetonitrile, 14.9 gm. (0.09 mole) in 200ml. of anhydrous diethyl ether. A gentle reflux is maintained during theaddition which requires 1/2 to 1 hour. After complete addition and anadditional 15 minutes at reflux, the reaction mixture is cooled andpoured onto a mixture of 50 ml. of concentrated hydrochloric acid and200 gms. of ice using good mixing. Upon warming the ether is removed bydistillation and the residue heated at 70°-100° C. for 1 hour. Theproduct is extracted with two portions, 250 ml. each of ether, the ethersolution dried over anhydrous magnesium sulfate and the solvent removed.Any of the reactants, i.e., halide and nitrile, are separated from theketone by fractional distillation under reduced pressure along withby-products.

In a similar procedure, the following ketones are prepared:

1-(2-Methylphenyl)-4-phenylpentan-2-one;

1-(4-t-Butylphenyl)-5-(4-isopropylphenyl)-pentan-3-one;

2-(3-Methylphenyl)-8-(2-isopropylphenyl)-octan-4-one;

1-(3-Methylphenyl)-4-(4-n-butylphenyl)-2-pentanone;

1,4-Di-(4-isopropylphenyl)-2-butanone;

1-Phenyl-3-(4-t-butylphenyl)acetone;

1-(3,4-Dimethylphenyl)-5-(4-isopropylphenyl)-3-pentanone;

2,6-Diphenyl-4-heptanone.

EXAMPLE C Preparation of N,N-Di-(2,3-dihydroxypropyl)trimethylenediamine

Bis-(2,3-dihydroxypropyl)amine (16.5 g., 0.1 mole) and acrylonitrile(6.4 g., 0.12 mole) is mixed in an ice bath and then warmed to roomtemperature. After standing for 2 hours, the mixture was then heated at45° C.-55° C. for 3 hours. The excess acrylonitrile is removed by gentlewarming under reduced pressure. The residue was taken up in ethylalcohol, mixed with sponge nickel catalyst and hydrogenated under 200psi hydrogen using good agaitation. After filtration of catalyst thesolvent and excess acrylonitrile is removed by stripping under reducedpressure to leave the product.

EXAMPLE D Preparation ofN,N,N'-Tri-(2,3-dihydroxypropyl)trimethylenediamine

N,N-di-(2,3-dihydroxypropyl)trimethylenediamine (11.1 g., 0.05 mole) isdissolved in 125 ml. of methanol and heated under reflux with agitation.Glycidol (3.7 g., 0.05 mole) is added dropwise over a period of 1.5 hourand the solution mixed an additional hour at 60° C.-80° C. The methylalcohol and other volatiles are removed by stripping under reducedpressure to leave the product suitable for use in the next steps.

EXAMPLE E Preparation of1,1,5-Tri-(2,3-dihydroxypropyl)-1,5,9-triazanonane

An aliquot of the residual oil from Preparation D (5.9 g., 0.02 mole) ismixed with acrylonitrile (2.75 g., 0.05 mole) at room temperature andthen warmed at 50° C.-60° C. for 10-15 hours. The excess acrylonitrileis removed by stripping under reduced pressure and the residual oiltaken up in 50 ml. of ethanol, mixed with 2 g. of sponge nickel catalystand shaken under a hydrogen atmosphere of 200 psi for 6 hours. Themixture is filtered free of catalyst and the solvent removed bydistillation. The product could be brought to analytical purity bychromatography on a silica gel column.

EXAMPLE 1 Preparation of1-[1,5-Di-(4-isopropylphenyl)-3-pentyl]-1,5,9-triazanone

1,5-Di-(4-isopropylphenyl)-3-pentanone (12.88 g., 0.04 mole) and3,3'-iminobispropylamine (26.2 g., 0.20 mole) in 250 ml. toluene isheated at reflux overnight with a Dean-Stark water separator. The cooledsolution is concentrated under reduced pressure. The residue isdissolved in ethanol and hydrogenated with 1.5 g. PtO₂ at roomtemperature and 40 psi hydrogen pressure. The platinum catalyst isfiltered off and the ethanol removed under vacuum. The residual oil isdissolved in ether and the ether solution washed several times withwater to remove the excess 3,3'-iminobispropylamine. The ether extractsare dried over anhydrous sodium sulfate and concentrated under vacuum toleave the polyamine as a colorless oil.

The oil is dissolved in ether and hydrogen chloride gas is bubbled intothe solution until no further precipitation occurs. The ether isevaporated under reduced pressure to leave the product as a solid whichis digested with hot isopropyl alcohol. The solids are collected byfiltration and dried under vacuum at 70° C. to give a colorless product,1-[1,5-di-(4-isopropylphenyl)-3-pentyl] -1,5,9-triazanonetrihydrochloride, m.p. 265° C.-267° C.

In an analogous manner from the ketones and the amines set forth below,there are prepared the following compounds of this invention.

                                      TABLE II                                    __________________________________________________________________________    Ketone       Amine        Product           M.P.°                      __________________________________________________________________________                                                C.                                1,7-Di-(4-t-butylphenyl)-                                                                  N,N'-bis-(3-aminopropyl)-                                                                  1-[1,7-Di-(4-t-butylphenyl)-                                                                    258°-259° C.        4-heptanone  1,3-propanediamine                                                                         4-heptyl]-1,5,9,13-tetraaza-                                                  tridecane tetrahydrochloride                        1,7-Di-(2-methyl-5-t-                                                                      N,N' -bis-(3-aminopropyl)-                                                                 1-[1,7-Di-(2-methyl-5-t-butyl-                                                                  259°-260° C.        butylphenyl)-4-heptanone                                                                   1,3-propanediamine                                                                         phenyl)-4-heptyl]-1,5,9,13-                                                   tetraazatridecance tetra-                                                     hydrochloride                                       1,5-Di-(4-methylphenyl)-                                                                   3,3'-Iminobis(propylamine)                                                                 1-[1,5-Di-(4-methylphenyl)-3-                                                                   --                                3-pentanone               pentyl]-1,5,9-triazanonane                          1,5-Di-(2,4,6-trimethyl-                                                                   3,3'-Iminobis(propylamine)                                                                 1-[1,5-Di-(2,4,6-trimethyl-                                                                     258°-260° C.        phenyl)-3-pentanone       phenyl)-3-pentyl]-1,5,9-                                                      triazanonane trihydrochloride                       1,7-Di-(4-t-butylphenyl)-                                                                  3,3'-Iminobis(propylamine)                                                                 1-[1,7-Di-(4-t-butylphenyl)-4-                                                                  246°-247° C.        4-heptanone               heptyl]-1,5,9-triazanonane                                                    trihydrochloride                                    1,7-Di-(2-methyl-5-t-                                                                      3,3'-Iminobis(propylamine)                                                                 1-[1,7-Di-(2-methyl-5-t-butyl-                                                                  255°-257° C.        butylphenyl)-4-heptanone  phenyl)-4-heptyl]-1,5,9-tri-                                                  azanonane trihydrochloride                          1,7-Di-(4-isopropylphenyl)-                                                                3,3'-Iminobis(propylamine)                                                                 1-[1,7-Di-(4-isopropylphenyl)-                                                                  237°-239° C.        4-heptanone               4-heptyl]-1,5,9-triazanonane                                                  trihydrochloride                                    1,7-Di-(4-t-butylphenyl)-                                                                  1,3-Diamino-2-propanol                                                                     1-[1,7-Di-(4-t-butylphenyl)-                                                                    267°-269° C.        4-heptanone               4-heptyl]-3-hydroxy-1,5-                                                      diazapentane dihydrochloride                        1,5-Di-(4-t-butylphenyl)-                                                                  3,3'-Iminobis(propylamine)                                                                 1-[1,5-Di-4-t-butylphenyl)-                                                                     274°-275° C.        acetone                   3-pentyl]-1,5,9-triazanonane                                                  trihydrochloride                                    1,7-Di-(4-isopropylphenyl)-                                                                Triethylenetetramine                                                                       1-[1,7-Di-(4-isopropylphenyl)-                                                                  250°-252° C.        4-heptanone               4-heptyl]-1,4,7,10-tetra-                                                     azadecane tetrahydrochloride                        1,7-Di-(4-t-butylphenyl)-                                                                  Triethylenetetramine                                                                       1-[1,7-Di-(4-t-butylphenyl)-                                                                    275°-276° C.        4-heptanone               4-heptyl]-1,4,7,10-tetra-                                                     azadecane tetrahydrochloride                        1,7-Di-(2-methyl-5-t-                                                                      Triethylenetetramine                                                                       1-[1,7-Di-(2-methyl-5-t-butyl-                                                                  272°-274° C.        butylphenyl)-4-heptanone  phenyl)-4-heptyl]-1,4,7,10-                                                   tetrazadecane tetrahydrochloride                    1,5-Di-(4-isopropylphenyl)-                                                                Triethylenetetramine                                                                       1-[1,5-Di-(4-isopropylphenyl)-                                                                  269°-270° C.        3-petanone                3-pentyl]-1,4,7,10-tetra-                                                     azadecane tetrahydrochloride -1,3-Di-(4-Isopropy                              lphenyl)-         Triethylenetetramine 1-[1,3-Di                                                -(4-isopropylphenyl)- --          acetone                   2-propyl]-1,4,7,10-tetra-                                                     azadecane tetrahydrochloride                        1,3-Di-(4-t-butylphenyl)-                                                                  Triethylenetetramine                                                                       1-[1,3-Di-(4-t-butylphenyl)-                        acetone                   2-propyl]-1,4,7,10-tetra-                                                     azadecane tetrahydrochloride                        1,3-Di-(4-isopropyl-                                                                       3,3'-Iminobis(propylamine)                                                                 1-[1,3-Di-(4-isopropylphenyl)-                      phenyl)acetone            2-propyl]-1,5,9-triazanonane                                                  trihydrochloride                                    1,3-Di-(4-t-butylphenyl)-                                                                  3,3'-Iminobis(propylamine)                                                                 1-[1,3-Di-(4-t-butylphenyl)-                        acetone                   2-propyl]-1,5,9-triazanonane                                                  trihydrohydrochloride                               1,9-Diphenyl-5-nonane-                                                                     N,N'-bis-(3-aminopropyl)-                                                                  1,9-Diphenyl-5-nonyl-1,5,9,13-                      diphenyl     1,3-propanediamine                                                                         tetrazatridecane tetrahydrochloride                 1,5-Diphenyl-3-pentanone                                                                   3,3'-Iminobis(propylamine)                                                                 1,5-Diphenyl-3-pentyl-1,5,9-                                                  triazanonane trihydrobromide                        Dibenzylketone                                                                             3,3'-Iminobis(propylamine)                                                                 1,3-Diphenyl-2-propyl-1,5,9,13-                                               tetrazatridecane tetrahydrochloride                 1,7-Diphenyl-4-heptanone                                                                   3,3'-Iminobis(propylamine)                                                                 1,7-Diphenyl-4-heptyl-1,5,9-                                                  triazanonane trihydrochloride                       1,7-Di-(4-ethylphenyl)-4-                                                                  1,3-Diamino-2-propanol                                                                     1,7-Di-(4-ethylphenyl)-4-heptyl-                    heptanone                 3-hydroxy-1,5-diazapentane di-                                                hydrochloride                                       1,5-Di-(2-isopropylphenyl)-                                                                3,3'-Iminobis(propylamine)                                                                 1,5-Di-(2-isopropylphenyl)-                         3-pentanone               3-pentyl-1,5,9-triazanonane                                                   trihydrobromide                                     1,9-Di-(2-ethylphenyl)-5-                                                                  Triethylenetetramine                                                                       1,9-Di-(2-ethylphenyl)-5-                           nonane                    nonyl-1,4,7,10-tetraaza-                                                      decane tetrahydrochloride                           1-(3-Methylphenyl)-4-(4-                                                                   3,3'-Methyliminobis(propyl-                                                                1-[1-(3-Methylphenyl)-4-                            n-butylphenyl)-2-pentanone                                                                 amine)       (4-n-butylphenyl)-2-pentyl]-                                                  5-methyl-1,5,9-triazanonane                         1,4-Di-(4-isopropylphenyl)-                                                                Tris-(2-aminoethyl)amine                                                                   1-[1,4-Di-(4-isopropylphenyl)-                      2-butanone                2-butyl]-4-(2-aminoethyl)-1,                                                  4,7-triazaheptane                                   1-Phenyl-3-(4-t-butylphenyl)-                                                              Dipropylenetriamine                                                                        N-[(1-Phenyl-3-(4-t-butylphenyl)-                   acetone                   propyl]dipropylenetriamine                          1-(3,4-Dimethylphenyl)-5-                                                                  Spermine     1-[1-(3,4-Dimethylphenyl)-5-                        (4-isopropylphenyl)-3-    (4-isopropylphenyl)-3-pentyl]-                      pentanone                 1,5,10,14-tetraazatetradecane                       2,6-Diphenyl-4-heptanone                                                                   1-(2-hydroxyethyl)-1,5,8-                                                                  1-(2,6-Diphenyl-4-heptyl)-8-(2-                                  triazaoctane hydroxyethyl)-1,4,8-triazaoctane                    Dibenzylketone                                                                             1-(2-hydroxypropyl)-5-                                                                     1-(1,3-Diphenyl-2-propyl)-5-                                     hydroxymethyl-1,5,9-                                                                       hydroxymethyl-9-(2-hydroxy-                                      triazanonane propyl)-1,5,9-triazanonane                          __________________________________________________________________________

EXAMPLE 2 Preparation of1-[1,5-Di-(4-isopropylphenyl)-3-pentyl]-1,4,7,10-tetrazadecane

1,5-Di-(4-Isopropylphenyl)-3-pentanone (0.02 mole) andtriethylenetetramine (0.10 mole) in 150 ml. of toluene is heated atreflux overnight with a Dean-Stark water separator. The toluene is thenremoved under vacuum. The residual oil dissolved in 25 ml. isopropanolis added dropwise to sodium borohydride (1.90 g., 0.05 mole, excess)suspended in 50 ml. isopropanol. After complete addition, the reactionmixture is heated at reflux for one hour. The isopropanol is evaporatedunder reduced pressure, the residue treated with water and the aqueousmixture extracted well with ether. The combined ether extracts areback-washed with water, a saturated sodium chloride solution, dried overanhydrous sodium sulfate and concentrated under vacuum to leave thepolyamine product as a clear oil 7.4 g. (90%).

The oil is dissolved in ether and the solution cooled in an ice-waterbath. Hydrogen chloride gas is bubbled into the solution until nofurther precipitate is formed. The solid is collected by filtration,washed with a small amount of ether, and dried under vacuum to leave thepolyamine tetrahydrochloride as a colorless product.

EXAMPLE 3 1-[1,7-Di-(4-Methylphenyl)-4-heptyl]-1,4,8-triazaoctane

A mixture of 1,7-di-(4-methylphenyl)-4-heptanone (0.03 mole) and1,2-diaminoethane (12.0 g., 0.20 mole) in 250 ml. ethanol is heated atreflux overnight. The cooled reaction mixture is hydrogenated with PtO₂at room temperature and 40 psi hydrogen pressure. The platinum catalystis filtered off and the ethanol removed under reduced pressure. Theresidual oil is dissolved in ether and the ether solution washed severaltimes with water to remove the excess diaminoethane. The ether extractsare dried over anhydrous sodium sulfate and concentrated under vacuum toleave a colorless oil, 11.2 g. (100%).

The oil is dissolved in 20 ml. tert-butanol and chilled to 0° C.-5° C.in an ice-water bath. Acrylonitrile (1.75 g., 2.2 ml., 0.033 mole) isadded dropwise over a 5-minute period. The reaction mixture is allowedto warm up to room temperature and is then heated at 60° C. overnight.The t-butanol was removed under reduced pressure. The residual oil wasdissolved in 150 ml. glacial acetic acid and hydrogenated wth PtO₂ atroom temperature and 40 psi hydrogen pressure. The platinum catalyst isfiltered off and the acetic acid removed under vacuum. The residue isdissolved in ether and made basic with 10% sodium hydroxide. The ethersolution is washed with water, dried over anhydrous sodium sulfate andconcentrated under reduced pressure.

EXAMPLE 4 Preparation of1-[1,5-Di-(phenyl)-3-pentyl]-5-(2,3-dihydroxypropyl)-1,5,9-triazanonane

1,5-Di-(phenyl)-3-pentanone (4.8 g., 0.02 mole) and3,3'-(2,3-dihydroxypropylimino)bispropylamine (20.5 g., 0.10 mole),(obtained by the catalytic hydrogenation of dicyanoethylatedglycerylamine), in 150 ml. of toluene is heated at reflux overnight witha Dean-Stark water separator. The cooled solution is concentrated underreduced pressure. The residue is dissolved in ethanol and hydrogenatedwith PtO₂ at room temperature and 40 psi hydrogen pressure. The platinumcatalyst is filtered off and the ethanol removed under vacuum. Theresidue is dissolved in ether and the ether solution washed severaltimes with water to remove the excess3,3'-(2,3-dihydroxypropylimino)bispropylamine. The ether extracts aredried over anhydrous sodium sulfate and concentrated to leave thepolyamine product.

In a like manner and using analogous quantities, but employingN,N-di-(2,3-dihydroxypropyl)trimethylenediamine and1,1,5-tri-(2,3-dihydroxypropyl)-1,5,9-triazanonane instead of3,3'-(2,3-dihydroxypropylimino)bispropylamine there are preparedrespectivelyN-[1,5-di-(phenyl)-3-pentyl]-N'-di-(2,3-dihydroxypropyl)trimethylenediamine,and1-[1,5-di-(phenyl)-3-pentyl]-5-(2,3-dihydroxypropyl)-9,9-di-(2,3-dihydroxypropyl)-1,5,9-triazanonane.

EXAMPLE 5 Preparation of1-[1,5-Di-(phenyl)-3-pentyl]-5-(2,3-dihydroxypropyl)-9-(1,3-dihydroxy-2-propyl)-1,5,9-triazanonane

1-[1,5-Di-(phenyl)-3-pentyl]-5-(2,3-dihydroxypropyl)-1,5,9-triazanonane(0.43 g., 0.001 mole) and 1,3-dihydroxyacetone (9 g., 0.1 mole) in 100ml. of chloroform is heated at reflux with a water separator connecteduntil 1.8 ml. of water is collected (8-12 hours). The chloroform andexcess 1,3-dihydroxyacetone are removed by distillation under reducedpressure. The residue is taken up in 75 ml. of ethanol, mixed with 1 gm.of platinum oxide and hydrogenated at 40 psi hydrogen pressure withshaking at room temperature. The catalyst is removed by filtration andethyl alcohol by distillation to leave a product which can be purifiedby column chromatography using silica gel and development with methylalcohol containing ammonium hydroxide.

In an analogous manner but starting withN-[1,7-di-(4-methylphenyl)-4-heptyl]ethylenediamine, there is obtainedN-[1,7-di-(4-methylphenyl)-4-heptyl]-N'-(1,3-dihydroxy-2-propyl)ethylenediamine.

EXAMPLE 6 Preparation of1-[1,7-Di-(phenyl)-4-heptyl]-4,8,8-tri-(2,3-dihydroxypropyl)-1,4,8-triazaoctane

1-[1,7-Di-(phenyl)-4-heptyl]-1,4,8-triazaoctane (0.37 g., 0.01 mole) isdissolved in 50 ml. of methanol and heated under reflux with agitation.Glycidol (15 g., 0.2 mole) is added dropwise over a period of 1.5 to 2hours. After complete addition, the reaction mixture is stirred anadditional two hours at 90° C.-100° C. The methyl alcohol is removed bystripping under reduced pressure and excess glycidol by distillation at1 mm. pressure. The residue could be further purified by conversion tothe trihydrochloride salt in ethyl alcohol with dry hydrogen chlorideand fractional crystallization. The free base may then be liberated fromits salt by resin ion exchange or neutralization with agueous sodiumhydroxide.

In an analogous manner using the following diphenyl polyamines, thereare obtained the following products.

    ______________________________________                                        Polyamine      Product                                                        ______________________________________                                        1-[1,5-Di-(phenyl)-3-                                                                        1-[1,5-Di-(phenyl)-3-pentyl]-                                  pentyl]-3,7-dihydroxy-                                                                       3,7-dihydroxy-5-(2,3-dihydroxy-                                1,5,9-triazanonane                                                                           propyl)-9,9-di-(2,3-dihydroxy-                                                propyl)-1,5,9-triazanonane                                     1-[1,5-Di-(phenyl)-3-                                                                        1-[1,5-Di-(phenyl)-3-pentyl]-                                  pentyl]-1,4,7-triaza-                                                                        4-(2,3-dihydroxypropyl)-7,7-                                   heptane        di-(2,3-dihydroxypropyl)-1,4,7-                                               triazaheptane                                                  1-[1,5-Di-(phenyl)-3-                                                                        N-[1,5-Di-(phenyl)-3-pentyl]-                                  pentyl]ethylenediamine                                                                       N',N'-di-(2,3-dihydroxypropyl)-                                               ethylenediamine                                                ______________________________________                                    

EXAMPLE 7 Preparation of1-Amino-3-[1,5-di-(phenyl)-3-pentylamino]-2-propanol

A solution of 1,5-di-(phenyl)-3-pentanone (9.5 g., 0.04 mole) in 50 cc.of anhydrous ethanol is added dropwise over about 20 minutes to astirred solution of 1,3-diamino-2-hydroxypropane (25 g., 0.27 mole) in200 cc. of ethanol. The resulting mixture is then heated at reflux forabout two hours, allowed to cool, 1.0 g. platinum oxide added, and themixture reduced under a 40 psi hydrogen atmosphere until hydrogen uptakeceases. The mixture is then filtered from the catalyst, concentrated invacuo to remove the ethanol, the residue taken up in ether (250 cc.),washed with water, dried over sodium sulfate, filtered and concentratedin vacuo to yield the product1-amino-3-[1,5-di-(phenyl)-3-pentylamino]-2-propanol.

Preparation of the dipropionate salt is carried out in the same manneras is the dihydrochloride in Example 1 except instead of hydrochloricacid there is used at least 2 moles of propionic acid per mole of freediamine.

Preparation of the dihydrochloride is achieved by adding to an ethersolution of the free amine an excess of isopropanol saturated withanhydrous hydrogen chloride, or by bubbling into an ether-isopropanolsolution of the amine dry hydrogen chloride until the solution issaturated. Excess ether is boiled away, fresh isopropanol added, boiledaway to a small volume whereby an oil separates. The solvent is decantedfrom the oil, the oil admixed with a small amount of fresh ether,diluted with isopropanol, the volatiles boiled away until the productseparates again, and the process repeated. The product is then rinsedwith isopropanol, dissolved in ether, filtered and concentrated to aproduct and allowed to solidify.

In addition to the compounds specifically set forth in the foregoingexamples, each of the respective ketones set forth in Preparations A andB when reacted with the individual amines set forth in the foregoingspecification especially at pages 10 and 11 according to the method setforth in Example I produce the entire range of compounds describedaccording to this invention as embodied in Formula I.

What is claimed is:
 1. A compound of the formula: ##STR10## where R ishydrogen or loweralkyl; each R₁ is alike or different and is C₁ to C₄alkylene; ##STR11## and R₂ is 2-hydroxy-1,3-trimethylene, or R₁ aspreviously defined;R₃ is hydrogen, C₁ to C₄ alkyl, C₂ to C₄ aminoalkyl,C₁ to C₄ hydroxyalkyl, or C₂ to C₄ dihydroxyalkyl; R₄ is2-hydroxy-1,3-trimethylene, or R₁ as previously defined; R₅ is hydrogen,aminoethyl, aminopropyl, C₁ to C₄ hydroxyalkyl, or C₂ to C₄dihydroxyalkyl; and R₆ is hydrogen, C₁ to C₄ hydroxyalkyl or C₂ to C₄dihydroxyalkyl.
 2. A compound according to claim 1 where R₁ ismethylene.
 3. A compound according to claim 1 where R₁ is ethylene.
 4. Acompound according to claim 1 where R₁ is trimethylene.
 5. A compoundaccording to claim 1 where Z is ##STR12##
 6. A compound according toclaim 1 where Z is --(CH₂)₂ NH₂.
 7. A compound according to claim 1where Z is ##STR13##
 8. A compound according to claim 1 where Z is CH₂CHOHCH₂ NH₂.
 9. A compound according to claim 1 where Z is (CH₂)₃ NH₂.10. A compound of the formula: ##STR14## where each A is alike ordifferent and is ##STR15## each R is alike or different and is hydrogenor loweralkyl; R₁ is methylene, ethylene, trimethylene ortetramethylene;and where Z is: --(CH₂)₃ NH(CH₂)₃ NH₂ ; --(ch₂)₂ nh(ch₂)₂nh(ch₂)₂ nh₂ ; --(ch₂)₃ nch₃ (ch₂)₃ nh₂ ; --ch₂ chohch₂ nh₂ ; --(ch₂)₂nh₂ ; --(ch₂)₃ nh₂ ; and acid addition salts thereof.
 11. A compoundaccording to claim 10 where each A is 4-isopropylphenyl.
 12. A compoundaccording to claim 10 where each A is 4-t-butylphenyl.
 13. A compoundaccording to claim 10 where each A is 2-methyl-5-t-butylphenyl.
 14. Acompound according to claim 10 where each A is 2,4,6-trimethylphenyl.15. The compound according to claim 10,1-[1,5-di-(4-isopropylphenyl)-3-pentyl]-1,5,9-triazanonane and itstrihydrochloride salt.
 16. The compound according to claim 10,1-[1,7-di-(t-butylphenyl)-4-heptyl]-1,5,9-triazanonane and itstrihydrochloride salt.
 17. The compound according to claim 10,1-[1,7-di-(2-methyl-5-t-butylphenyl)-4 -heptyl]-1,4,7,10-tetrazadecaneand its tetrachloride salt.
 18. The compound1-[1,5-di-(4-t-butylphenyl)-3-pentyl]-1,5,9-triazanonane and itstrihydrochloride salt.
 19. The compound according to claim 10,1-[1,7-di-(4-t-butylphenyl)-4-heptyl]-1,4,7,10-tetrazadecane and itstetrahydrochloride salt.
 20. The compound according to claim 10,1-[1,7-di-(2-methyl-5-t-butylphenyl)-4-heptyl]-1,5,9-triazanonane andits trihydrochloride salt.
 21. The compound according to claim 10,1-[1,7-bis-(4-t-butylphenyl)-4-heptyl]-1,5,9,13-tetrazatridecane and itstetrahydrochloride salt.
 22. The compound according to claim 10,1-[-1,5-di-(2,4,6-trimethylphenyl)-3-pentyl]-1,5,9-triazanonane and itstrihydrochloride salt.